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Shrinking options for antibiotics in gonorrhea

Gonorrhea is a common sexually transmitted infection (STI). It can cause inflammation of affected tissue—usually in the anogenital tract and throat. Gonorrhea can contribute to pelvic inflammatory disease in women, can lead to infertility and can be transmitted to an infant during pregnancy, leading to blindness.

In the early 20th century, the treatment for gonorrhea was initially sulpha drugs and later penicillin. However, the bacteria that cause gonorrhea (N. gonorrhoeae) eventually developed resistance to these drugs. Subsequent oral antibiotics were developed and used to treat gonorrhea, but N. gonorrhoeae has developed reduced susceptibility or, in some cases, resistance to them. Below is a brief history of gonorrhea treatments in the United States—when they were introduced and when the development of significant resistance occurred (broadly similar trends happened in Canada and Europe around the same period):

  • Sulpha drugs were introduced in the 1930s and failed in many cases by the mid-1940s.
  • Penicillin was introduced in the mid-1940s and was no longer recommended by 1989.
  • Spectinomycin was introduced in 1961 and began to fail in the 1980s.
  • Ciprofloxacin and similar drugs were introduced in the early 1980s and were no longer recommended by the end of that decade.
  • Azithromycin was introduced in the early 1990s and was no longer recommended by 2007 (as single-drug therapy).

Ceftriaxone was introduced about 40 years ago and has been an important antibiotic for serious infections of the abdomen, lungs, brain and other tissues. As other antibiotics encountered increasing resistance from gonorrhea-causing bacteria, ceftriaxone began to be used more frequently. Today, ceftriaxone is the leading antibiotic for gonorrhea treatment in Canada and many high-income countries. Ceftriaxone is given as a single dose by intramuscular injection in many countries, and in Japan and China via intravenous infusion.

Increasing doses

Over the past 40 years, gonorrhea-causing bacteria have become less susceptible to ceftriaxone. For instance, in the early 1980s, clinical trials found that a single dose of 125 mg of ceftriaxone was able to cure gonorrhea. However, by 2022, doses of 500 mg were being routinely used in the U.S. What’s more, even higher doses—1,000 mg—were recommended in Europe and Japan. In some parts of China, researchers have documented extremely high doses of ceftriaxone (greater than 1,000 mg) being used for gonorrhea treatment.

Given the historical trend of how gonorrhea-causing bacteria respond to antibiotics, it is possible that in the future N. gonorrhoea may require even higher doses of ceftriaxone or longer courses of this drug than what is routinely used in Europe or North America. Reports of resistance to ceftriaxone by gonorrhoea-causing bacteria remain rare but have been slowly increasing in the past decade. It seems obvious that new antibiotics for the treatment of gonorrhea (and other bacteria) are needed, but it is not clear if candidate treatments currently in late-stage clinical trials will be successful and achieve regulatory approval. For instance, two antibiotics—delafloxacin and solithromycin—once considered promising candidates for gonorrhea treatment, yielded disappointing clinical trial results in the past decade.

Antibiotic development

According to a report of antibiotic development commissioned by the Biotechnology Innovation Organization (BIO), most antibiotics (82%) approved by regulatory authorities were developed prior to the year 2000. The report states that most of these antibiotics “are facing eventual loss in efficacy due to resistance developed by bacterial strains encountering these treatments in the population. For the next generation of [antibiotics] to fill the gap, there needs to be a well-funded and appropriately rewarded biotech ecosystem for translational science to reach the clinic and beyond.”

Underfunded

The BIO report found that over the past decade, antibiotic development programs were only able to raise US $2.3 billion. In the same decade, companies working on the development of anticancer drugs were able to raise US $38 billion. Not surprisingly, there are now fewer clinical trials of antibiotics compared to about a decade ago.

Reasons for the insufficient funding

Most new clinical drug development is done by the pharmaceutical industry. However, the BIO report found that large companies have been leaving the field of antibiotic development. This appears to be driven by poor prospects of profitability for new antibiotics.

Some other key findings from the BIO report are as follows:

  • Most antibiotics have lost patent protection and are now relatively cheap generic drugs.
  • New powerful antibiotics will probably be reserved for limited use, perhaps primarily in hospitals. Patients may only get new antibiotics if treatment with older ones fails.
  • If approved, new antibiotics will likely only be used for a relatively short period of time (in each person). Furthermore, hospitals may ration their use in an attempt to preserve their efficacy.
  • Pharmaceutical companies, being for-profit corporations, will generally want to maximize the price of new antibiotics, while public drug formularies (that subsidize the cost of medicines and have limited budgets) will want to pay lower prices.

The New York Times has noted that in the past five years, financial issues have dogged some companies that focused on antibiotic development. For instance, three biotech companies that were developing antibiotics have had to file for bankruptcy and/or creditor protection because of disappointing results from clinical trials and/or sales revenue.

These and other factors have had a negative impact on the scale of development of new antibiotics. A recent report by a team of scientists from several countries has largely arrived at similar conclusions to the BIO report. Although antibiotics are in development, some scientists have noted that many of the ones in late-stage clinical trials are not truly innovative but analogues of existing antibiotics. As they are analogues, they may not be effective against all strains of bacteria resistant to existing antibiotics.

Perhaps innovative models for funding and eliciting interest in antibiotic development are needed. Such models could include intensified partnerships that involve governments, universities, foundations and the private sector.

A global threat

Research by scientists who study the ability of germs to resist treatment—this ability is called antimicrobial resistance (AMR)—suggests that worldwide about five million people died in 2019 because of drug-resistant germs. What’s more, research commissioned by the government of the UK suggests that drug-resistant microbes could kill as many as 10 million people each year by 2050. Many of these deaths would be caused by drug-resistant bacteria.

To help prevent further deaths from drug-resistant bacteria, scientists and policy makers will need to deploy a combination of the following strategies:

  • community-based programs to ensure access to sanitation and clean water
  • developing vaccines to prevent key bacterial infections
  • reducing unnecessary use of antibiotics
  • increasing funding for the development of new antibiotics

Back to gonorrhea

Although there are at least two experimental antibiotics—zoliflodacin and gepotidacin—in phase III clinical trials for gonorrhea treatment, these trials may not be finished until mid-to-late 2023. The data collected then have to be analysed and submitted to regulatory authorities for their review and hopefully approval. Thus, even if these drugs are found to be generally safe and effective for gonorrhea treatment, they may not be available until 2024.

In the meantime, based on lab experiments with gonorrhea-causing germs and antibiotics, some researchers have proposed that older antibiotics approved for other infections or other classes of drugs approved for other conditions be repurposed and tested in clinical trials for their potential to treat gonorrhea. Such drugs include the following:

  • acetazolamide
  • lefamulin (Xenleta)
  • ertapenem (Invanz)
  • ertapenem + moxifloxacin
  • gentamicin + moxifloxacin

The next report in this issue of TreatmentUpdate is about a clinical trial that compared the effectiveness of different antibiotics primarily for the treatment of anogenital gonorrhea.

—Sean R. Hosein

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